REVIEW ARTICLE

Defining Phenotypes in COPD: An Aid to Personalized Healthcare

Andrea Segreti • Emanuele Stirpe •

Paola Rogliani • Mario Cazzola

� Springer International Publishing Switzerland 2014

Abstract The diagnosis of chronic obstructive pulmon-

ary disease (COPD) is based on a post-bronchodilator

fixed forced expiratory volume in 1 second (FEV1)/forced

vital capacity (FVC) \70 % ratio and the presence of

symptoms such as shortness of breath and productive

cough. Despite the simplicity in making a diagnosis of

COPD, this morbid condition is very heterogeneous, and

at least three different phenotypes can be recognized: the

exacerbator, the emphysema–hyperinflation and the

overlap COPD–asthma. These subgroups show different

clinical and radiological features. It has been speculated

that there is an enormous variability in the response to

drugs among the COPD phenotypes, and it is expected

that subjects with the same phenotype will have a similar

response to each specific treatment. We believe that

phenotyping COPD patients would be very useful to

predict the response to a treatment and the progression of

the disease. This personalized approach allows identifi-

cation of the right treatment for each COPD patient, and

at the same time, leads to improvement in the effective-

ness of therapies, avoidance of treatments not indicated,

and reduction in the onset of adverse effects. The objec-

tive of the present review is to report the current knowl-

edge about different COPD phenotypes, focusing on

specific treatments for each subgroup. However, at pres-

ent, COPD phenotypes have not been studied by

randomized clinical trials and therefore we hope that well

designed studies will focus on this topic.

Key Points

Chronic obstructive pulmonary disease (COPD) is a

heterogeneous disease or disorder. It is important to

classify and group patients, as subjects within the

same subgroup/phenotype are likely to have a similar

progression of disease and response to treatments.

There are three different COPD phenotypes: the

exacerbator, the emphysema–hyperinflation and the

overlap COPD–asthma.

The development of different pharmacological and

non-pharmacological treatment options has proven

that clinical response differs according to the

characteristics of the disease. Although a specific

therapy may not yet be identified for each phenotype,

there is a clear need to move toward personalized

treatment of COPD.

1 Introduction

Chronic obstructive pulmonary disease (COPD), a complex

syndrome with many pulmonary and extra-pulmonary

components, includes different phenotypes, defined as ‘‘a

single or combination of disease attributes that describe

differences between individuals with COPD as they relate

to clinically meaningful outcomes (symptoms, exacerba-

tions, response to therapy, rate of disease progression, or

A. Segreti � E. Stirpe � P. Rogliani � M. Cazzola (&)

Unit of Respiratory Medicine, Department of System Medicine,

University of Rome Tor Vergata, via Montpellier 1,

00131 Rome, Italy

e-mail: mario.cazzola@uniroma2.it

Mol Diagn Ther

DOI 10.1007/s40291-014-0100-9

death)’’ [1]. As recommended by Global Initiative for

Chronic Obstructive Lung Diseases (GOLD) guidelines,

diagnosis of COPD is very easy because it is based on a

reduced post-bronchodilator forced expiratory volume in 1

second (FEV1)/forced vital capacity (FVC) ratio below the

fixed value of 70 % [2]. However, COPD is a heteroge-

neous disease, likely a disorder. Celli and colleagues

hypothesized that FEV1 is not enough to estimate severity

of COPD, and that a multidimensional approach would better

grade the disease and predict the outcome with respect to the

use of the FEV1 alone [3]. Therefore, it is important to group

patients in phenotypes because subjects included in the same

subgroup/phenotype are expected to have similar disease,

progression of disease and response to treatments.

According to classification of Miravitlles and col-

leagues, it is possible to identify at least three different

COPD phenotypes: the exacerbator, the emphysema–

hyperinflation and the overlap COPD–asthma [1]. Frequent

exacerbators are patients that experience two or more

exacerbations of COPD per year [4], and have typically

chronic bronchitis, defined clinically as chronic productive

cough for 3 months in each of 2 successive years in a

patient in whom other causes of productive chronic cough

have been excluded [5]. The emphysema–hyperinflation

phenotype is characterized by parenchymal destruction

with consequent hyperinflation, and dyspnea and intoler-

ance to exercise are the predominating symptoms [1].

Emphysema is defined pathologically as the presence of

permanent enlargement of the airspaces distal to the ter-

minal bronchioles, accompanied by destruction of their

walls and without obvious fibrosis [6]. The third pheno-

type, COPD–asthma overlap syndrome, is characterized by

incompletely reversible airflow obstruction (COPD), i.e.,

reduced post-bronchodilator FEV1, in addition to an

increased variability of airflow, which can be determined

by increased bronchodilator responsiveness or bronchial

hyper-responsiveness [7].

It has been speculated that clinical features of different

COPD phenotypes may be associated with morphological

changes at chest high-resolution computed tomography

(HRCT) and a different response to treatments, including

inhaled corticosteroids (ICSs) and bronchodilators [8]. As a

matter of fact, Kitaguchi and colleagues demonstrated that

COPD patients with A phenotype (without emphysema)

and M phenotype (emphysema with bronchial wall thick-

ening), compared with E phenotype (emphysema without

bronchial wall thickening), were significantly associated

with reversibility response to treatment with ICSs and

sputum eosinophilia, suggesting that the morphological

phenotypes of COPD show several clinical characteristics

and different responsiveness to pharmacological treatments

[9]. A summary of principal features of each phenotype is

reported in Table 1.

2 Phenotyping Chronic Obstructive Pulmonary Disease

(COPD)

2.1 Frequent Exacerbator Phenotype

Exacerbations of COPD have an important role in the

natural history of the disease. An exacerbation of COPD is

defined as ‘‘a sustained worsening of the patient’s condi-

tion, from the stable state and beyond normal day-to-day

variations, that is acute in onset and necessitates a change

in regular medication in a patient with underlying COPD’’

[10]. Exacerbations in 50–70 % of cases are due to respi-

ratory infections (including bacteria, atypical organisms

and respiratory viruses), in 10 % are due to environmental

pollution (depending on season and geographical place-

ment), and up to 30 % are of unknown etiology [11]. In the

ECLIPSE (Evaluation of COPD Longitudinally to Identify

Predictive Surrogate Endpoints) observational study,

exacerbations were more frequent and more severe with the

progression of COPD, and the variable most strongly

associated with exacerbations during the first year of fol-

low-up was a history of exacerbations [4]. According to

GOLD guidelines, patients in group C and D are at high

risk of exacerbations. Both groups typically include

patients with severe and very severe airflow limitation, but

patients in group D have more symptoms than those

included in group C [2]. However, the ECLIPSE study has

documented that frequent exacerbations can also be present

in those patients with an FEV1 higher than 50 % predicted

[4]. The pathophysiology underlying the frequent exacer-

bator phenotype includes increased airway and systemic

inflammation, dynamic lung hyperinflation, changes in

lower airway bacterial colonization, increased susceptibil-

ity to viral infection and increased risk from comorbid

extrapulmonary diseases [12].

A post-hoc analysis of the POET-COPD (Prevention Of

Exacerbations with Tiotropium in COPD) trial showed that

the frequent exacerbator phenotype was closely associated

with exacerbation-related hospitalizations, which in turn

were associated with poorer survival [13]. These data

suggest that it is mandatory to properly treat this distinct

clinical subgroup, to reduce the risk of future

exacerbations.

In accordance with GOLD guidelines, the first-choice

treatment of patients at high risk of exacerbations includes

a fixed combination of ICS plus long-acting b2-agonist

(LABA) and/or long-acting muscarinic antagonist (LAMA)

[2]. ICSs are indicated in patients with more severe disease

and frequent exacerbations, and their use in stable COPD

improves lung function, decreases the rate of exacerba-

tions, and seems to improve the survival when combined

with bronchodilators, but must be weighed against the

potential for increased vulnerability to pneumonia [14].

A. Segreti et al.

Bronchodilators are used to improve COPD symptoms

such as dyspnea, and reduce hyperinflation secondary to

airflow limitation. However, recent studies suggest that

bronchodilators may also decrease the risk of COPD

exacerbations, reducing the lung hyperinflation and

increasing inspiratory capacity, and it is also possible that

they exert direct or indirect effects on lung inflammation

[15].

Another treatment option for this subgroup of patients

might be the administration of roflumilast. This oral anti-

inflammatory drug is a highly selective phosphodiesterase-

4 (PDE-4) inhibitor, and its use is indicated for treatment of

severe COPD associated with chronic bronchitis and fre-

quent exacerbations, as an add-on to bronchodilators [16].

Two placebo-controlled, double-blind, randomized clinical

trials have shown that roflumilast 500 lg daily can reduce

the rate of exacerbations in COPD patients with severe

airflow limitation [17]. In a post-hoc analysis of pooled

data from two 1-year, placebo-controlled roflumilast

(500 lg once daily) studies in patients with symptomatic

COPD and severe airflow obstruction published by Wed-

zicha and colleagues, 32 % of COPD patients treated with

roflumilast still experienced frequent exacerbations at year

1 compared with 40.8 % of patients treated with placebo.

The authors concluded that treatment with roflumilast may

shift patients from the frequent to the more stable infre-

quent exacerbator state [18]. This finding could question

the existence of a frequent exacerbator phenotype.

Another important aspect to consider is that lower air-

way bacterial colonization in stable COPD patients can

induce bronchial inflammation and infections, and conse-

quently can modulate the character and frequency of

exacerbations [19]. For this reason, a long-term adminis-

tration of antibacterials to prevent exacerbations of COPD

has been advocated. Different clinical trials have demon-

strated that floroquinolones and macrolides have antin-

flammatory and immunomodulatory effects, and their

administration was associated with a reduction in COPD

exacerbations [20–24]. However, currently there is inade-

quate evidence to recommend routine prophylactic long-

term antibacterial therapy in this group of patients to pre-

vent exacerbations [25]. The analysis of literature also

suggests that the use of bacterial lysates represents a

potentially effective approach in preventing exacerbations

of COPD, but almost all trials conducted to date have been

of poor quality and, above all, poorly designed [26].

2.2 COPD–Emphysema Phenotype

Emphysema is defined pathologically as the presence of

permanent enlargement of the airspaces distal to the ter-

minal bronchioles, accompanied by destruction of their

walls and without obvious fibrosis [6]. Subjects with doc-

umented emphysema have lower FEV1, FEV1/FVC ratio,

and lower carbon monoxide transfer coefficient (KCO)

compared with subjects without emphysema and, in chest

radiograph and HRCT scan, emphysema scores are higher

and, conversely, chronic bronchitis scores are lower.

Dyspnea, exercise intolerance and lower body mass index

(BMI) are the clinical hallmarks of this phenotype [27].

Table 1 Principal characteristics of COPD phenotypes

Phenotype Pathophysiological features Imaging features Key treatments

Frequent exacerbator Two or more exacerbations of

COPD per year

Bronchial wall thickening Inhaled corticosteroids

Bronchodilators

Presence of chronic bronchitis Roflumilast

Bacterial lysates

Emphysema–hyperinflated Parenchymal destruction with

consequent hyperinflation

Emphysema Bronchodilators

Lung volume reduction surgery

Dyspnea and intolerance to

exercise are the predominating

symptoms

Pulmonary rehabilitation programs

Reduced diffusing capacity (KCO)

Low rate of exacerbations

Asthma–COPD overlap Incompletely reversible airflow

obstruction (COPD)

Mixed features of asthma and

COPD, i.e., bronchial wall

thickening and emphysema

Bronchodilators

Inhaled corticosteroids

Increased variability of airflow Other therapies generally used for treatment

of asthma and COPD (e.g., omalizumab,

antileukotrienes and theophyllines)

Increased levels of sputum

eosinophils

Preserved diffusing capacity (KCO)

Low rate of exacerbations

COPD chronic obstructive pulmonary disease, KCO carbon monoxide transfer coefficient

COPD Phenotypes

Hyperinflation is usually considered to be an elevation

above normal values of resting functional residual capacity

(FRC) or end expiratory lung volume (EELV), and is

caused by both static and dynamic processes. The reduction

in elastic recoil due to emphysema is responsible for static

hyperinflation, while dynamic hyperinflation occurs when

minute ventilation is enhanced to accommodate increased

respiratory demands [28].

The phenotype characterized by emphysema without

bronchial wall thickening presents a lower rate of exacer-

bations compared with COPD phenotypes characterized by

emphysema with bronchial wall thickening, and bronchial

wall thickening in absence of emphysema [8]. These data

indicate that the COPD–emphysema phenotype is less

prone to experiencing exacerbations of COPD unless it is

present simultaneously with bronchial wall thickening, a

feature of chronic bronchitis. Furthermore, it has been

demonstrated that pulmonary hyperinflation is associated

with low grade systemic inflammation. In fact, inspiratory

capacity reduction, an index of an increase in residual

volume, is associated with high serum levels of C Reactive

Protein (CRP) in stable COPD patients [29].

Bronchodilators induce a relaxation of smooth muscle tone

in airways and consequently reduce the flow limitation and

promote lung emptying, as demonstrated by increase in

inspiratory capacity and reduction of residual volume at spi-

rometry [30]. Long-acting bronchodilators are the foundation

of the pharmacological treatment of COPD because they

improve symptoms, exercise capacity and, consequently,

improve the state of health as perceived by the patient [31].

Other treatments such as pulmonary rehabilitation programs

reduce lung hyperinflation and improve tolerance, gas

exchange and perceived symptoms during effort [32].

The current guidelines recommend the use of more than

one bronchodilator in order to achieve an additional effect,

without increasing adverse effects in patients with poorly

controlled symptoms in spite of treatment with a bron-

chodilator [2]. In COPD–emphysema phenotype patients,

the use of double bronchodilator therapy versus broncho-

dilator monotherapy offers an added functional benefit with

reduction of the rescue medication needed, and improve-

ment of symptoms and quality of life [33]. Anti-inflam-

matory treatment with ICSs and roflumilast has not been

shown to be as effective in the emphysema–hyperinflation

phenotype [34, 35]. Lung volume reduction surgery (LVRS)

may be particularly indicated in COPD patients with

emphysema–hyperinflation. The NETT (National Emphy-

sema Treatment Trial) has provided substantial evidence that

treating hyperinflation in emphysema can improve exercise

tolerance, quality of life, and survival [36].

Lastly, pulmonary rehabilitation programs in patients

with emphysema significantly improve exercise capacity,

symptoms and quality of life [37].

2.3 Asthma–COPD Overlap Syndrome Phenotype

Zeki and colleagues analyzed the prevalence of the various

obstructive airway diseases in a small cohort of general

pulmonary clinic patients and found that prevalence of

asthma–COPD overlap syndrome was 15.8 % [38]. In

another study, the utilization of a simple questionnaire

showed that the overlap between asthma and COPD com-

prised about 20 % of patients with COPD, and that this

syndrome included a higher proportion of COPD patients

with atopy and smoking asthmatics [39]. It has been

demonstrated that subjects with the overlapping diagnoses

of COPD and asthma have increased disease severity, are

more than three times as likely to be frequent exacerbators

and nearly twice as likely to experience severe respiratory

exacerbations, and have more gas trapping on expiratory chest

CT scans and greater subsegmental wall area on inspiratory

CT scans, compared with subjects with COPD alone [40].

Furthermore, patients with the overlap syndrome, in

comparison with subjects with COPD alone, have higher

peripheral and sputum eosinophil counts, preserved dif-

fusing capacity, higher prevalence of bronchial thickening

on chest HRCT and better reversibility response to treat-

ment with ICS. In particular, the increases in FEV1 after

treatment with ICS correlated significantly with sputum

eosinophil counts and the grade of bronchial wall thick-

ening [41].

COPD is characterized by neutrophilic inflammation,

macrophages and CD4? and CD8?T cells [42]. However,

it has been observed that in some patients with COPD (e.g.,

asthma-COPD overlap syndrome), the eosinophilic

inflammation plays an important role as well. A random-

ized, double-blind, crossover study investigated whether

the sputum characteristics of COPD patients were corre-

lated with the response to 2 weeks of treatment with

prednisolone. The authors of this study reported that

patients with eosinophilic airway inflammation had a good

response to corticosteroids [43], indicating that eosino-

philic inflammation in COPD patients may be predictive of

a response to steroid therapy. This hypothesis is supported

by the observation that the minimization of the eosinophilic

airway inflammation is associated with a reduction in

severe exacerbations of COPD [44].

3 COPD Phenotypes and Biomarkers

‘‘A biomarker refers to the measurement of any molecule

or material (e.g., cells, tissue) that reflects the disease

process’’ [45]. An ideal biomarker should be lung-specific,

reproducible, easy to assess in large numbers of patients,

and validated in a large, well characterized cohort of

patients and controls [46]. The identification of biomarkers

A. Segreti et al.

specific for each phenotype would facilitate the classifica-

tion of COPD patients and would provide prognostic

information and predict drug response [47].

The application of the -OMIC approach such as

genomics, proteomics and metabolomics for the collection

and analysis of data, might allow identification of robust,

reliable and reproducible biomarkers in many human dis-

eases, including COPD [48, 49]. In effect, the application

of proteomics and metabolomics in COPD is already

available and, in combination with genomic studies, will

likely identify novel candidate biomarkers [50].

In the lungs of COPD patients there is an imbalance

between oxidants and antioxidants, with resultant defective

repair processes, DNA damage and lung injury [51]. The

metabolomics profiles of volatile organic compounds

(VOCs) were examined in the breath by an electronic nose,

among the different COPD phenotypes. This study dem-

onstrated that exhaled molecular profiling, combined with

clinical features, functional parameters, and chest CT

scanning, was able to distinguish between the different

COPD subphenotypes [52]. Moreover, in another study,

ultra-high-performance liquid chromatography/quadruple-

time-of-flight mass spectrometry techniques were used to

identify a large number of metabolite markers among dif-

ferent COPD phenotypes, and these predictive models were

able to differentiate very accurately the subjects with the

emphysematous phenotype of COPD from those with

COPD without emphysema [53]. Another study performed

in COPD patients assessed the association between serum

concentrations of biomarkers with CT findings. Particu-

larly, the presence of airway thickening was directly

associated with levels of interleukin (IL)-6, IL-13, IL-2

receptor, interferon-gamma (IFNc) and CRP, but inversely

correlated with epidermal growth factor receptor (EGFR)

and regulated on activation normal T cell expressed and

secreted (RANTES). Instead, biomarkers directly associ-

ated with the presence of emphysema were IL-6 and matrix

metalloproteinase-7 (MMP-7), while tumor necrosis factor-

alpha (TNFa) was inversely related to emphysema severity

[54]. Also, the number of eosinophils, MMP-9 and the

MMP-9/tissue inhibitor of metalloproteinase-1 (TIMP-1)

ratio in sputum were higher in COPD patients with HRCT-

confirmed emphysema, compared with those without

emphysema [55]. Moreover, patients with emphysema

presented elevated concentrations of markers of systemic

inflammation (i.e., serum systemic oxidative stress and

plasma fibrinogen levels), compared with COPD patients

without emphysema [56].

In the ECLIPSE study, some biomarkers, inter alia, an

increase in platelet count, white-cell count, neutrophil

count, and serum fibrinogen, high-sensitivity CRP, che-

mokine ligand 18 (CCL-18) and surfactant protein D (SP-

D), have been shown to predict acute exacerbations of

COPD [4]. In the same study, it was demonstrated that

white-cell count and the systemic levels of IL-6, CRP, IL-

8, fibrinogen, CCL-18/pulmonary and activation-regulated

chemokine (PARC) and SP-D were higher in patients who

died during the 3-year period of follow-up. Moreover, non-

survivors were older and had more severe airflow limita-

tion, increased dyspnea, higher BODE score (BMI, airflow

obstruction, dyspnea and exercise), more emphysema, and

higher rates of comorbidities and history of hospitalizations

[57]. Another interesting finding is that patients with

asthma–COPD overlap syndrome had significantly lower

blood concentrations of nitrites/nitrates (NOx), indicating

decreased systemic oxidant activity in this group of

patients compared with other phenotypes of COPD [58].

Again, in COPD patients, sputum concentrations of IL-5

were associated with sputum eosinophilia, a marker of

asthma–COPD overlap syndrome, and were attenuated

after oral corticosteroid therapy [59].

All these results confirm the usefulness of biomarkers in

clinical practice, because they contribute to the classifica-

tion of COPD patients into phenotypes, and help to predict

response to therapy, disease progression and mortality.

4 Conclusions

International guidelines try to simplify the diagnosis and

treatment of patients affected by COPD. However, there is

an enormous variability in the response to drugs between

patients suffering from this morbid condition. In our

opinion, the classification of COPD patients into subgroups

provides prognostic information and it is expected that

subjects with the same phenotype will have a similar

response to each specific treatment. Publication of large

trials such as TORCH (TOwards a Revolution in COPD

Health) and UPLIFT (Understanding Potential Long-term

Impacts on Function with Tiotropium) has refocused

attention away from simply treating current symptoms and

improving quality of life (current control) to focusing on

preventing future exacerbations, reducing mortality and

preventing disease progression (prevention of future risk)

[60].

The GOLD and National Institute for Health and Care

Excellence (NICE) guidelines estimate disease severity on

the basis of multi-dimensional assessment. Inhaled bron-

chodilators are the cornerstone of pharmacotherapy in both

sets of guidelines, with combined ICS/LABA inhalers

being reserved for more severe disease. Smoking cessation

and pulmonary rehabilitation remain key interventions, with

NICE recommending pulmonary rehabilitation at hospital

discharge after an acute exacerbation of COPD [2, 61].

The concept of phenotype applied to COPD focuses on

the definition of different types of patients with prognostic

COPD Phenotypes

and therapeutic significance: the varied host response and

heterogeneous nature of COPD can explain failure of

treatment. Identification and targeted treatment of clinical

and pathological phenotypes within the broad spectrum of

COPD may therefore improve the outcomes [62].

The goal of phenotyping is to identify patient groups

with unique prognostic or therapeutic characteristics.

Although this approach represents an ideal construct, it is

known that each phenotype may be etiologically hetero-

geneous and that any individual may manifest multiple

phenotypes [63].

For this reason, it is fundamental to identify the char-

acteristics of patients that predict response to drugs used to

manage COPD. Individualized therapy allows administra-

tion of the right treatment to the right patient, increasing, in

this way, the subject’s response to therapy, avoiding

treatments not indicated and reducing the onset of adverse

effects.

The development of different pharmacological and non-

pharmacological treatment options has demonstrated that

the clinical response can be different according to the

characteristics of the disease [1].

Although a specific therapy may not be ultimately

identified for each phenotype, there is a clear need to move

toward personalized treatment in COPD, although we must

honestly admit that, unlike in asthma, in COPD the need

for personalized medicines is not currently clearly defined

[64].

A better understanding of the multiple dimensions of

COPD and its relationship to other diseases is very relevant

and of high current interest. Recent theoretical (scale-free

networks), technological (high-throughput technology,

biocomputing) and analytical improvements (systems

biology) provide tools capable of addressing the com-

plexity of COPD. The information obtained from the

integrated use of those techniques will be eventually

incorporated into routine clinical practice [65].

Because the diversity of phenotypes of each condition is

better understood, clinicians will be presented with

opportunities to evolve from a ‘one size fits all’ approach to

personalized approaches, with the ultimate goal of

improving care and reducing potential adverse effects from

unnecessary therapies [66]. This means that we might take

on a more personalized treatment not only according to the

severity of the airflow obstruction, but also conditioned by

the clinical phenotype.

Actually, international guidelines, a part the recent

Spanish guidelines [67], do not differentiate COPD patients

into phenotypes and tend to homogenize patients with

different diseases, thus reaching different results.

Unfortunately, there are no randomized clinical studies

that evaluated the influence of COPD phenotypes in terms

of response to treatment and disease progression. This

means that there is an urgent need for well designed clin-

ical studies focused on COPD phenotypes.

Acknowledgements and Disclosures None.

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